Discoveries & Impact (October 2022)

Discoveries & Impact highlights select scientific discoveries per section across the Department of Internal Medicine. See the complete publications report in "Related Documents."

Yale Study Enhances Understanding of Blood Disorders

Yale investigators have discovered that hematopoietic stem and progenitor cells (HSPCs) behavior is in part inherited from signaling pathways in endothelial cells (ECs) that line blood vessels.

The results were published Sept. 30 in the preprint server bioRxiv.

Adults produce billions of mature blood cells per day through a process called hematopoiesis. However, the signaling pathways that regulate HSPC production remain widely unknown. In their study, Stefania Nicoli, PhD, associate professor at Yale School of Medicine, and Joey Ghersi, PhD, a postdoctoral associate in the Nicoli lab, screened for hematopoiesis defects in zebrafish embryos to determine the specific role of microRNAs (miRNAs) in driving EC behaviors.

“Our findings illustrate how endothelial signaling shape hematopoietic stem cells heterogeneity formation during embryonic development and may lead to further insights in the battle against cancer,” said Ghersi.

In blood cancers such as leukemia and lymphoma, autologous stem cell transplant is a common procedure where the patient’s stem cells are collected and stored. After the patient undergoes chemotherapy, the stem cells that were destroyed by the treatment are replaced. However, the existence of a diverse pool of HSPCs poses a unique challenge. Prior to the formation of HSCs, endothelial signaling shapes this diversity. These findings may provide avenues to investigate novel interventions for blood cancer patients.

Joey J. Ghersi, Gabriel Baldissera, Jared Hintzen, Stephanie A. Luff, Siyuan Cheng, Ivan Fan Xia, Christopher M. Sturgeon, Stefania Nicoli. Hematopoietic stem and progenitor cell heterogeneity is inherited from the embryonic hemogenic endothelium. bioRxiv 2022.09.28.509963; doi: https://doi.org/10.1101/2022.09.28.509963

Consider Vonoprazan for Helicobacter pylori Infection

Helicobacter pylori infection can cause peptic ulcers and stomach cancers. Proton pump inhibitors are used to treat this infection, but given relatively low rates of eradication with current regimens, new and effective treatments are needed for patients with Helicobacter pylori.

Researchers from Yale School of Medicine, Michigan Medicine, University of Bordeaux, the Guardian Angel Research Center, Phathom Pharmaceuticals, and University of Tennessee College of Medicine conducted a phase 3 study to see if drug regimens using vonoprazan would improve treatment of Helicobacter pylori as compared to those using proton pump inhibitors.

The main findings were that “vonoprazan-based triple and dual regimens were non-inferior to lansoprazole-based triple therapy” and “superior to proton pump inhibitor-based triple therapy in clarithromycin-resistant strains and in the overall study population” for the eradication of Helicobacter pylori.

To learn more about the patient demographics and information on each tested therapy, read Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial in Gastroenterology.

Chey WD, Mégraud F, Laine L, López LJ, Hunt BJ, Howden CW. Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial. Gastroenterology 2022, 163(3): 608-619. doi: 10.1053/j.gastro.2022.05.055. PMID: 35679950.

New Data on the Scholarly Output of Physician Assistant Educators

Although scholarly output has long been a metric used to measure the productivity of physicians, data on published works of physician assistant (PA) educators remain far more limited. A team led by Alexandria Garino, PhD, PA-C, assistant professor and director of the Yale Physician Associate Program, sought to remedy this gap in a new study published in the Journal of Physician Assistant Education.

The authors analyzed the publication records of hundreds of PA-credentialed educators, including articles published as far back as the early 1970s. The results ultimately showed that the quantity of published works and rates of citation were higher for professor and associate-level faculty as well as PhD-prepared faculty, and underscored the need for more publications and higher citation rates in order to advance the PA educator literature.

The findings comprise an important body of data that can be used in the faculty promotion and career development of physician assistants. Read more in “Publish or Perish: A Cross-Sectional, Bibliometric Analysis of Physician Assistant Faculty Publications.”

Garino A, Wang L, Min EA. Publish or Perish: A Cross-Sectional, Bibliometric Analysis of Physician Assistant Faculty Publications. J Physician Assist Educ. 2022 Jun 1;33(2):87-93. doi: 10.1097/JPA.0000000000000417. Epub 2022 Apr 15. PMID: 35427260.

Medical Students Reflect on Increased Diversity in Institutional Portraits

Historically, oil portrait paintings of white men have made up nearly all of the artwork in the Sterling Hall of Medicine, a prominent building within the Yale School of Medicine (YSM) campus. Recently, updates were made to the building’s portraiture to feature more diversity in gender and background.

In a new qualitative study, researchers from the YSM, Johns Hopkins University School of Medicine, and Yale New Haven Hospital conducted interviews with second- to fourth-year medical students at Yale, asking for their reflections on both the original and updated artwork.

Four common themes emerged from the collection of student interviews. Interviewees described artwork as reflective of institutional values and responded positively to the increase in diverse representation. Students also expressed concerns over performativity and noted how students took initiative to create communities of belonging for themselves.

The team concluded that institutional portraiture has a considerable impact on students' experiences of medical school by contributing to racialized and gendered aspects of the environment. This finding suggests that re-evaluating visual culture in educational institutions may be worthwhile. Read more about the study in the Journal of General Internal Medicine.

Konkwo C, Fitzsousa E, Chan SM, Muhammad M, Anderson N, Reisman A. Revisiting the Exhibits-Medical Student Reflections on Changes to the Institutional Portraiture at a US Medical School. J Gen Intern Med. 2022 Sep 21. doi: 10.1007/s11606-022-07803-y. Epub ahead of print. PMID: 36131052.

Evaluate Appropriateness of Antibiotics for Homebound Older Adults

Homebound older adults are often unable to receive care in an office setting. This challenge is more complicated if the homebound older adult is living with dementia. If infections arise in these patients, there are many factors that must be considered during clinical decision making.

Researchers at Yale School of Medicine, Veterans Affairs Connecticut Healthcare System in West Haven, Conn., Brown University School of Public Health, and the Providence Veterans Affairs Medical Center, conducted a cohort study of patients living with dementia who received home-based primary care over a five-year period to look at prescriptions for antibiotics and diagnosis codes for those prescription fills. They found that antibiotic prescriptions were widespread and potentially inappropriate in this population, and urged further investigation into antibiotic stewardship. Read more in Open Forum Infectious Diseases.

Datta R, Fried T, O'Leary JR, Zullo AR, Allore H, Han L, Juthani-Mehta M, Cohen A. National Cohort Study of Homebound Persons Living With Dementia: Antibiotic Prescribing Trends and Opportunities for Antibiotic Stewardship. Open Forum Infectious Diseases 2022, 9(9): ofac453. doi: 10.1093/ofid/ofac453. PMID: 36147594. PMCID: PMC9487603.

A New Class of Antifungals Targeting Vitamin B5 Utilization

Fungal infections represent a major threat to human health, responsible for an estimated 1.7 million annual deaths globally. The rise of multidrug-resistant fungal isolates presents a unique challenge in the medical management of patients with these infections. A new Yale paper published in Structure offers novel insights into a promising drug target for antifungal therapies.

The team of researchers from Yale School of Medicine, Yale Center for Molecular Discovery, University of Oklahoma Health Sciences Center, Seattle Structural Genomics Center for Infectious Disease, and University of Washington’s Center for Emerging & Re-emerging Infectious Disease solved the crystal structure of the first fungal pantothenate kinase enzyme PanK. This enzyme catalyzes a crucial first step in the utilization of pantothenic acid (vitamin B5) for the biosynthesis of coenzyme A, an essential molecule in major cellular processes. Importantly, PanK activity is encoded by a single PanK gene in all fungi that have been genetically sequenced thus far, making it a powerful target for the development of new therapeutics.

The findings identify key features of PanK, including the mechanisms responsible for its major activities. The data have already aided in the identification of new compounds that halt the growth of Candida species, also reported in the paper. Learn more in “High Resolution Crystal Structure and Chemical Screening Reveal Pantothenate Kinase as a New Target for Antifungal Development.”

Gihaz S, Gareiss P, Choi JY, Renard I, Pal AC, Surovsteva Y, Chiu JE, Thekkiniath J, Plummer M, Hungerford W, Montgomery ML, Hosford A, Adams EM, Lightfoot JD, Fox D 3rd, Ojo KK, Staker BL, Fuller K, Ben Mamoun C. High-resolution crystal structure and chemical screening reveal pantothenate kinase as a new target for antifungal development. Structure. 2022 Sep 21:S0969-2126(22)00354-9. doi: 10.1016/j.str.2022.09.001. Epub ahead of print. PMID: 36167065.

Evaluating Penicillin Allergy During Pregnancy

Allergy verification testing should be offered during pregnancy, as most women do not have a true penicillin allergy. A study by Yale researchers aimed to evaluate a hospital-wide multidisciplinary program introduced in August 2020 to identify, refer, evaluate, and test pregnant women with unverified penicillin allergies and assess its association with maternal and neonatal outcomes. The study documented the feasibility, safety, and clinical benefit of an outpatient penicillin allergy referral program for pregnant women. Read the original research article in the American Journal of Obstetrics and Gynecology MFM.

Kwah JH, Burn MS, Liao J, Cate J, Son M. Outpatient penicillin allergy evaluation during pregnancy and associated clinical outcomes. American Journal of Obstetrics & Gynecology MFM 2022, 4(5): 100674. doi: 10.1016/j.ajogmf.2022.100674. PMID: 35691578.

New Tool Aids Clinical Decision-Making

The risk of dying of breast cancer persists for at least 20 years from diagnosis. Yale researcher and colleagues estimated the risk of death for women with invasive, non-metastatic, hormone receptor-positive breast cancer during this timeframe as well as competing risks of death. To aid clinical decision-making, they developed an interactive tool called ESTIMATE for exploring the Surveillance, Epidemiology, and End Results (SEER) registry to quantify residual risks of breast cancer-specific mortality (BCSM), non-BCSM and all-cause mortality in non-metastatic, hormone receptor-positive breast cancer patients at any time after diagnosis up to 20 years.

By providing population-based risks of BCSM, non-BCSM and all-cause mortality through 20 years after diagnosis, ESTIMATE can inform discussions about prognosis and aid clinical decision-making. Read more in the European Journal of Cancer.

Leone JP, Graham N, Tolaney SM, Leone BA, Freedman RA, Hassett MJ, Leone J, Vallejo CT, Winer EP, Lin NU, Tayob N. Estimating long-term mortality in women with hormone receptor-positive breast cancer: The 'ESTIMATE' tool. European Journal Of Cancer (Oxford, England : 1990) 2022, 173: 20-29. doi: 10.1016/j.ejca.2022.06.029. PMID: 35841843.

Addressing the Exclusion of Patients with CKD from Cancer Drug Trials

Many cancer drugs are partially excreted through the kidney; the availability of accurate data on safe and effective dosing of these drugs in patients with chronic kidney disease (CKD) is essential to guide treatment decisions. Typically, during drug development, initial clinical studies include patients with normal or mildly impaired kidney function. In subsequent preregistration studies, a limited number of patients with more severe kidney dysfunction are included. Data obtained from patients with severe kidney dysfunction or end-stage kidney disease are particularly limited and could result in a manufacturer statement that the drug should not be used in patients with advanced kidney disease. This systematic exclusion of patients with CKD from cancer drug trials prevents their receiving optimal clinical care and raises questions of inclusion, diversity, and equity.

In addition, with an aging population, an increasing number of patients with CKD and cancer face these issues. In a review article, Yale nephrologist Mark Perazella, MD, and colleagues evaluate the scientific basis to exclude patients with chronic kidney disease from cancer trials and propose a strategy to address the problem.

Sprangers B, Perazella MA, Lichtman SM, Rosner MH, Jhaveri KD. Improving Cancer Care for Patients With CKD: The Need for Changes in Clinical Trials. Kidney International Reports 2022, 7(9): 1939-1950. doi: 10.1016/j.ekir.2022.06.005. PMID: 36090489. PMCID: PMC9458993.

International Consensus Statement on Obstructive Sleep Apnea

Faculty from Yale’s Pulmonary, Critical Care and Sleep Medicine section (Yale-PCCSM) in the department of internal medicine are among the multidisciplinary experts who produced an international consensus statement on obstructive sleep apnea (OSA). Their evaluation and interpretation of the literature on OSA consolidates and summarizes key factors that are important for the clinical management of OSA in adult patients. Knowledge gaps and opportunities for improvement include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy. Read the review article in the International Forum of Allergy & Rhinology.

Chang JL, Goldberg AN, Alt JA, Ashbrook L, Auckley D, Ayappa I, Bakhtiar H, Barrera JE, Bartley BL, Billings ME, Boon MS, Bosschieter P, Braverman I, Brodie K, Cabrera-Muffly C, Caesar R, Cahali MB, Cai Y, Cao M, Capasso R, Caples SM, Chahine LM, Chang CP, Chang KW, Chaudhary N, Cheong CSJ, Chowdhuri S, Cistulli PA, Claman D, Collen J, Coughlin K, Creamer J, Davis EM, Dupuy-McCauley KL, Durr ML, Dutt M, Ali ME, Elkassabany NM, Epstein LJ, Fiala JA, Freedman N, Gill K, Gillespie MB, Golisch L, Gooneratne N, Gottlieb DJ, Green KK, Gulati A, Gurubhagavatula I, Hayward N, Hoff PT, Hoffmann OMG, Holfinger SJ, Hsia J, Huntley C, Huoh KC, Huyett P, Inala S, Ishman S, Jella TK, Jobanputra AM, Johnson AP, Junna MR, Kado JT, Kaffenberger TM, Kapur VK, Kezirian EJ, Khan M, Kirsch DB, Kominsky A, Kryger M, Krystal AD, Kushida CA, Kuzniar TJ, Lam DJ, Lettieri CJ, Lim DC, Lin HC, Liu SYC, MacKay SG, Magalang UJ, Malhotra A, Maurer JT, May AM, Mitchell RB, Mokhlesi B, Mullins AE, Nada EM, Naik S, Nokes B, Olson MD, Pack AI, Pang EB, Pang KP, Patil SP, de Perck EV, Piccirillo JF, Pien GW, Piper AJ, Plawecki A, Quigg M, Ravesloot MJL, Redline S, Rotenberg BW, Ryden A, Sarmiento KF, Sbeih F, Schell AE, Schmickl CN, Schotland HM, Schwab RJ, Seo J, Shah N, Shelgikar AV, Shochat I, Soose RJ, Steele TO, Stephens E, Stepnowsky C, Strohl KP, Sutherland K, Suurna MV, Thaler E, Thapa S, Vanderveken OM, de Vries N, Weaver EM, Weir ID, Wolfe LF, Woodson BT, Won CHJ, Xu J, Yalamanchi P, Yaremchuk K, Yeghiazarians Y, Yu JL, Zeidler M, Rosen IM. International consensus statement on obstructive sleep apnea. International Forum Of Allergy & Rhinology 2022 doi: 10.1002/alr.23079. PMID: 36068685.